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The American Journal of Pathology Jan 2024Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms....
Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms. Although current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. Herein, these alterations parallel urodynamic disturbance reminiscent of lower urinary tract symptoms. Single-cell RNA-sequencing analysis of Pb-PRL mouse prostates revealed that their epithelium mainly includes low-androgen signaling cell populations analogous to Club/Hillock cells enriched in the aged human prostate. These intermediate cells are predicted to result from the reprogramming of androgen-dependent luminal cells. Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation, and stemness features. ATT prevented the growth of organoids generated by sorted Pb-PRL basal and LSC cells, the two major BPH-associated, androgen-independent epithelial cell compartments. Taken together, these results support cell plasticity as a driver of BPH progression and therapeutic resistance to androgen signaling inhibition, and identify antioxidant therapy as a promising treatment of BPH.
Topics: Male; Humans; Mice; Animals; Aged; Androgens; Prostate; Prostatic Hyperplasia; Antioxidants; Cell Plasticity; Hyperplasia; Lead; Mice, Transgenic; Prolactin; Epithelial Cells; Lower Urinary Tract Symptoms
PubMed: 37827216
DOI: 10.1016/j.ajpath.2023.09.010 -
International Journal of Pharmaceutics Sep 2009This study has explored the use of lipid-based formulations to enhance the oral bioavailability of the poorly water-soluble drug anethol trithione (ATT), and compared... (Comparative Study)
Comparative Study
This study has explored the use of lipid-based formulations to enhance the oral bioavailability of the poorly water-soluble drug anethol trithione (ATT), and compared the performance of different formulations. Two groups of lipid-based formulations, sub-microemulsion (SME) and oil solution, were prepared using short (SCT), medium (MCT) and long (LCT) chain triglycerides respectively; aqueous suspension was used as the reference formulation. In vitro and in vivo studies were conducted to investigate the impact of lipid composition and formulation on drug absorption. In vitro digestion was used to analyze lipid digestion rates and drug distribution/solubilization. After in vitro digestion, the performance rank order for drug solubilization was SCT
Topics: Administration, Oral; Anethole Trithione; Animals; Biological Availability; Chemistry, Pharmaceutical; Emulsions; Intestinal Absorption; Male; Rats; Rats, Sprague-Dawley; Solubility; Triglycerides
PubMed: 19508887
DOI: 10.1016/j.ijpharm.2009.06.001 -
Biochemical Pharmacology May 2014High homocysteine (Hcys) levels are suspected to contribute to the pathogenesis of cardiovascular disease and of other chronic conditions. Failure of B vitamins to...
High homocysteine (Hcys) levels are suspected to contribute to the pathogenesis of cardiovascular disease and of other chronic conditions. Failure of B vitamins to reduce the incidence of cardiovascular events while lowering the Hcys levels, has prompted the search for alternative treatments. We tested the ability of anethole dithiolethione (ADT) to lower the Hcys levels in rats and we explored possible underlying mechanisms. Parenteral administration of 10mg/kg ADT to normal rats for 3 days lowered the Hcys levels between 51.4% and 31.5% in kidneys, liver, testis and plasma. Concomitantly, glutathione (GSH) increased between 112% and 28% in kidneys, brain, liver and plasma whereas protein thiolation index decreased 30%. In hyperhomocysteinemic rats, the plasma Hcys levels dropped 70% following a single ip injection of 10mg/kg ADT, while they decreased 55% following oral administration of 2mg/kg/day ADT for one week. Significant additive effects occurred when sub-therapeutic doses of ADT and folic acid were used in combination. To test the possible mechanism(s) of these actions, we perfused isolated rat livers and kidneys with albumin-bound Hcys, the prevalent form of plasma Hcys, and physiological thiols and disulfides at different ratios. In both organ preparations, the elimination rate of albumin-bound Hcys was progressively faster as the amount of reduced thiols was increased in the perfusate. These findings indicate that ADT shifts the redox ratio of GSH and other thiols with their oxidized forms toward the reduced forms, thus favoring the dissociation of albumin-bound Hcys and its transfer to renal and hepatic cells for further processing.
Topics: Anethole Trithione; Animals; Dose-Response Relationship, Drug; Down-Regulation; Glutathione; Homocysteine; Kidney; Liver; Lung; Rats; Rats, Sprague-Dawley; Tissue Distribution; Up-Regulation
PubMed: 24637238
DOI: 10.1016/j.bcp.2014.03.005 -
European Journal of Pharmacology Jun 1997Astrocytes protect neurons against reactive oxygen species such as hydrogen peroxide, a capacity which reportedly is abolished following loss of the antioxidant... (Comparative Study)
Comparative Study
Astrocytes protect neurons against reactive oxygen species such as hydrogen peroxide, a capacity which reportedly is abolished following loss of the antioxidant glutathione. Anethole dithiolethione, a sulfur-containing compound which is used in humans, is known to increase cellular glutathione levels and thought thereby to protect against oxidative damage. In the present study we found that anethole dithiolethione increased the glutathione content of cultured rat striatal astrocytes. This effect was abolished by coincubation with the glutathione synthesis inhibitor buthionine sulfoximine. Nevertheless, in the presence of buthionine sulfoximine, despite the lack of an increase in the lowered glutathione level, anethole dithiolethione fully protected the astrocytes against the enhanced toxicity of hydrogen peroxide. Thus, apparently other mechanisms than stimulation of glutathione synthesis are involved in the compound's protective action in astrocytes. Considering the occurrence of lowered glutathione levels in neurodegenerative syndromes, we conclude that further evaluation of the therapeutic potential of anethole dithiolethione is warranted.
Topics: Anethole Trithione; Animals; Astrocytes; Cells, Cultured; Cholagogues and Choleretics; Corpus Striatum; Glutathione; Hydrogen Peroxide; Oxidative Stress; Rats; Rats, Wistar
PubMed: 9226421
DOI: No ID Found -
BMC Medical Research Methodology Jun 2022Real-life data consist of exhaustive data which are not subject to selection bias. These data enable to study drug-safety profiles but are underused because of their...
A data-driven pipeline to extract potential adverse drug reactions through prescription, procedures and medical diagnoses analysis: application to a cohort study of 2,010 patients taking hydroxychloroquine with an 11-year follow-up.
CONTEXT
Real-life data consist of exhaustive data which are not subject to selection bias. These data enable to study drug-safety profiles but are underused because of their temporality, necessitating complex models (i.e., safety depends on the dose, timing, and duration of treatment). We aimed to create a data-driven pipeline strategy that manages the complex temporality of real-life data to highlight the safety profile of a given drug.
METHODS
We proposed to apply the weighted cumulative exposure (WCE) statistical model to all health events occurring after a drug introduction (in this paper HCQ) and performed bootstrap to select relevant diagnoses, drugs and interventions which could reflect an adverse drug reactions (ADRs). We applied this data-driven pipeline on a French national medico-administrative database to extract the safety profile of hydroxychloroquine (HCQ) from a cohort of 2,010 patients.
RESULTS
The proposed method selected eight drugs (metopimazine, anethole trithione, tropicamide, alendronic acid & colecalciferol, hydrocortisone, chlormadinone, valsartan and tixocortol), twelve procedures (six ophthalmic procedures, two dental procedures, two skin lesions procedures and osteodensitometry procedure) and two medical diagnoses (systemic lupus erythematous, unspecified and discoid lupus erythematous) to be significantly associated with HCQ exposure.
CONCLUSION
We provide a method extracting the broad spectrum of diagnoses, drugs and interventions associated to any given drug, potentially highlighting ADRs. Applied to hydroxychloroquine, this method extracted among others already known ADRs.
Topics: Antirheumatic Agents; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Follow-Up Studies; Humans; Hydroxychloroquine; Prescriptions
PubMed: 35676635
DOI: 10.1186/s12874-022-01628-3 -
Bioorganic & Medicinal Chemistry Letters Sep 2022Oxidative stress and inflammation were considered to be the major mechanisms in liver damage caused by clofibrate (CF). In order to obtain lipid-lowering drugs with less...
Oxidative stress and inflammation were considered to be the major mechanisms in liver damage caused by clofibrate (CF). In order to obtain lipid-lowering drugs with less liver damage, the structure of clofibrate was optimized by O-desmethyl anetholtrithione and got the target compound clofibrate-O-desmethyl anetholtrithione (CF-ATT). CF-ATT significantly reduced the levels of plasma triglycerides (TG), total cholesterol (TC) in hyperlipidemia mice induced by Triton WR-1339. In addition, CF-ATT has a significantly protective effect on the liver compared with CF. The liver weight and liver coefficient were reduced. The hepatic function indexes were also decreased, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Histopathological examination of the liver revealed that inflammatory cell infiltration, nuclear degeneration, cytoplasmic loosening and hepatocyte necrosis were ameliorated by administration with CF-ATT. The hepatoprotective mechanism showed that CF-ATT significantly up-regulated Nrf2 and HO-1 protein expression and down-regulated p-NF-κB P65 expression in the liver. CF-ATT has obviously antioxidant and anti-inflammatory activity. These findings suggested that CF-ATT has significant hypolipidemia activity and exact hepatoprotective effect possibly through the Nrf2/NF-κB-mediated signal pathway.
Topics: Anethole Trithione; Animals; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clofibrate; Liver; Liver Diseases; Mice; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress
PubMed: 35697180
DOI: 10.1016/j.bmcl.2022.128844 -
Nanoscale Oct 2019To address the thereapeutic challenges in clinical cancer treatment and guarantee efficient and rapid intracellular delivery of drugs while evading efflux and...
To address the thereapeutic challenges in clinical cancer treatment and guarantee efficient and rapid intracellular delivery of drugs while evading efflux and chemotherapy resistance, herein, we designed a liposomal nanostructure equipped with superparamagnetic iron oxide nanoparticles (SPIOs) and anethole trithione (ADT, a hydrogen sulfide (HS) donor drug). At first, by spatially focused manipulation of the external static magnetic field (SMF), the SPIOs and ADT-loaded liposomes (SPIOs-ADT-LPs) could rapidly overcome the cell membrane barrier to enter the cytoplasm, which could be imaged by magnetic resonance imaging (MRI). Sequentially, the intracellular release of ADT drugs was triggered by enzymatic catalysis to generate acoustic-sensitive HS gas. At the beginning, during the production of HS at low concentrations, the cell membrane could be permeabilized to further increase the cellular uptake of SPIOs-ADT-LPs. The continued generation of HS gas bubbles, imaged by ultrasound (US) imaging, further enhanced the intracellular hydrostatic pressure (above 320 pN per cell) to physically unfold the cytoskeleton, leading to complete cell death. The magneto-acoustic approach based on SPIO-ADT-LPs as intracellular bubble reactors leads to improved anticancer cell efficacy and has potential applications for novel MRI/US dual image-guided bubble bursting of cancer cells.
Topics: Anethole Trithione; Hep G2 Cells; Humans; Hydrogen Sulfide; Liposomes; Magnetic Fields; Magnetic Resonance Imaging; Microbubbles; Nanoparticles; Neoplasms; Ultrasonography
PubMed: 31596307
DOI: 10.1039/c9nr07021d -
Antioxidants & Redox Signaling 2000Interaction between neutrophils and endothelial cells is one of the first steps in the functional response of polymorphonuclear neutrophils (PMN), and is necessary for...
Interaction between neutrophils and endothelial cells is one of the first steps in the functional response of polymorphonuclear neutrophils (PMN), and is necessary for their migration toward damaged tissues. PMN activation, leading to their adhesion to and migration between endothelial cells, is part of a complex phenomenon that can be altered in pathological situations such as the ischemia-reperfusion syndrome, in which large numbers of PMN are recruited to the tissue and release reactive oxygen species (ROS) near the vessel wall. ROS have been implicated in the pathogenesis of various inflammatory diseases. The increased adhesion of PMN to ROS-stimulated endothelial cells involves an increase in tyrosine phosphorylation of a tyrosine kinase focal adhesion kinase (p125FAK) and several cytoskeleton proteins, including paxillin and p130 cas. We examined the role of glutathione (GSH) in the regulation of this adhesion phenomenon and in the increased tyrosine phosphorylation induced by ROS. For this purpose we used anethole dithiolthione (ADT), which increases the glutathione synthesis by activating gamma-glutamyl-cysteine synthetase. We found that ADT reduced both PMN adhesion to ROS-stimulated human umbilical vein endothelial cells (HUVEC) and tyrosine phosphorylation of p125FAK and paxillin. ADT increased redox status by increasing intracellular GSH content in oxidized cells. These results show that GSH can reverse the effect of oxidation on tyrosine kinase activation and phosphorylation, and thus plays an important role in cell signaling. They also confirm the antioxidant activity of ADT.
Topics: Anethole Trithione; Antioxidants; Cell Adhesion; Cells, Cultured; Cytoskeletal Proteins; Endothelium, Vascular; Enzyme Activation; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Glutathione; Humans; Hypoxanthine; In Vitro Techniques; Neutrophils; Oxidation-Reduction; Oxidative Stress; Paxillin; Phosphoproteins; Phosphorylation; Protein-Tyrosine Kinases; Reactive Oxygen Species; Signal Transduction; Xanthine Oxidase
PubMed: 11213483
DOI: 10.1089/ars.2000.2.4-789 -
Journal of Neural Transmission (Vienna,... May 2006Anethole dithiolethione (ADT) is a clinically available, pluripotent antioxidant proposed as a neuroprotectant for Parkinson's disease (PD). Here, using extracts from... (Comparative Study)
Comparative Study
Anethole dithiolethione (ADT) is a clinically available, pluripotent antioxidant proposed as a neuroprotectant for Parkinson's disease (PD). Here, using extracts from cultured astrocytes, containing both monoamine oxidase (MAO) A and B activity, we demonstrate that ADT concentration-dependently inhibits MAO-B activity in a clinically relevant concentration range (0.03-30 microM, IC-50 = 0.5 microM) without affecting MAO A activity. Considering the alleged contribution of MAO activity in general, and MAO-B in particular, to oxidative stress and neurodegeneration in PD, our data further support the neuroprotective potential of ADT.
Topics: Analysis of Variance; Anethole Trithione; Animals; Animals, Newborn; Antioxidants; Astrocytes; Basal Ganglia; Cells, Cultured; Clorgyline; Dose-Response Relationship, Drug; Enzyme Activation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Rats
PubMed: 16252076
DOI: 10.1007/s00702-005-0350-0 -
Macromolecular Bioscience Nov 2015Back Cover: The micellar prodrugs of desmethyl anethole dithiolethione (ADT-OH) with different hydrolysis rates prepared from block copolymers having ADT-OH linked via...
Back Cover: The micellar prodrugs of desmethyl anethole dithiolethione (ADT-OH) with different hydrolysis rates prepared from block copolymers having ADT-OH linked via an ester bond using glycine and isoleucine linkers are presented. Micelles having a glycine linker inhibit proliferation of cancer cells. Further details can be found in the article by U. Hasegawa, N. Tateishi, H. Uyama, A. J. van der Vlies on page 1512.
Topics: Anethole Trithione; Antineoplastic Agents; Humans; Hydrolysis; Micelles; Neoplasms; Prodrugs
PubMed: 26502003
DOI: 10.1002/mabi.201570042